Actinic keratosis (AK) is a precancerous (premalignant) skin disorder caused by or associated with chronic exposure to radiant energy, such as sunlight. Actinic keratosis lesions are small, red, rough spots or lesions occurring on sun exposed areas of the skin. Actinic keratosis lesions possess many of the same cellular changes observed in a skin cancer called squamous cell carcinoma (SCC). Research shows that a mutated version of the p53 gene is found in sun-damaged cells in the body and is present in more than about 90% of people who have AK and squamous cell carcinomas. Although most actinic keratosis lesions do not actually become cancerous, some lesions can become malignant.
It is believed that actinic keratosis develops in skin cells called keratinocytes, which are the cells that constitute about 90% of the epidermis, the outermost layer of skin. Chronic sun exposure, over time, generates mutations in these cells and causes the cells to change in size, shape, the way they are organized, and the way they behave. In addition, the cellular damage can even extend to the dermis, the layer of skin beneath the epidermis.
Actinic keratoses (AKs) are common cutaneous lesions associated with chronic exposure to solar ultraviolet radiation (UVR). Frost C A and Green A C, Br J Dermatol 1994; 131:455-64. AKs and squamous cell carcinomas (SCCs) share histologic and molecular features; therefore, AKs are considered by some experts to be incipient SCCs. Cockerell C J, J Am Acad Dermatol 2000; 42(1Pt2):11-17. Although some AKs spontaneously regress and the risk of progression of an individual AK to an invasive SCC is low, AKs tend to be multifocal and recurrent. Since patients who present with multiple AKs may be at higher risk for developing an SCC, treatment of AKs is recommended. Glogau R G, J Am Acad Dermatol 2000; 42 (1Pt2):23-24; Criscione V D et al., Cancer 2009; 115:2523-30; Drake L A et al., J Am Acad Dermatol 1995; 32:95-98.
Actinic keratosis lesions generally measure in size between about 2 to about 6 millimeters in diameter. AK lesions can range in color from skin-toned to reddish and often have a white scale on top. On occasion, AK lesions will form into the shape of animal horns. When this occurs, the AKs are known as “cutaneous horns.”
People who are at higher risk for developing actinic keratosis tend to be fair-skinned and spend significant time outdoors, e.g., at work or at play, over the course of many years. AK lesions usually develop on those areas of the body that have been constantly exposed to the sun for years. Additionally, the skin often becomes wrinkled, mottled, and discolored from chronic sun exposure. Common locations for actinic keratosis include the face, ears, lips, balding scalp, back of the neck, upper chest, the tops of the hands and forearms. When AK lesions develop on the lips, the condition is known as actinic cheilitis. Actinic cheilitis can be characterized by a diffuse scaling on the lower lip that cracks and dries. In some cases, the lips will have a whitish discoloration on the thickened lip.
Actinic keratosis is generally more common after age 40, because actinic keratosis takes years to develop. However, even younger adults may develop actinic keratosis when living in geographic areas that are exposed to high-intensity sunlight year round, such as Florida and Southern California.
Actinic keratosis has become a significant health care issue in the United States of America. It is estimated that over 20 million Americans suffer from actinic keratosis, and that that number continues to grow. In fact, actinic keratosis is so common today that treatment for actinic keratosis ranks as one of the most frequent reasons people consult a dermatologist.
AK treatments can be divided into lesion-directed versus field-directed, and provider-administered and patient-administered treatments. In the United States, cryosurgery is the most common provider-administered treatment and is a lesion-directed therapy. Balkrishnan R et al., J Dermatolog Treat 2006; 17:162-66. Cryosurgery utilizes extreme cold to destroy tissue, including abnormal or diseased tissue, such as benign or malignant skin disorders (e.g., keratoses, warts, moles, skin tags, neuromas, and small skin cancers). While cryosurgery is appropriate for localized conditions, there is the possibility of damage to healthy tissues, including nerve tissues and blood vessels supporting healthy tissues. Side effects of cryosurgery include localized pain, redness or other discoloration, blisters, scabbing, and/or peeling.
One advantage of cryosurgery is the ability to tailor the treatment based on individual lesion characteristics, such as the degree of hypertrophy or hyperkeratosis. Efficacy, however, may vary depending on the length of freezing; in one study, individual lesion clearance rates varied from 39% with freeze times of less than 5 seconds to 83% with freeze times of greater than 20 seconds. That K E et al., Int J Dermatol 2004; 43:687-92. The trade-off for long freeze times, however, is an increased risk for hypopigmentation and greater discomfort during the procedure, particularly when many lesions are treated in a single session. As a lesion-directed therapy, cryosurgery fails to address the issue of “field cancerization” associated with UVR damage. Braakhuis B J et al., Cancer Res 2003; 63:1727-30. The skin around clinically apparent AKs is subject to the same UVR-induced damage as found in AKs, resulting in dysplastic lesions that are not clinically apparent, but which have been identified by biopsy or specialized imaging. Ulrich M et al., Dermatology 2010; 220:15-24; Ortonne J P et al., Exp Dermatol. 2010; 19:641-47. Over time, these “subclinical” lesions may progress to clinically apparent “new” AKs requiring further treatment, or even develop into de novo invasive SCCs. Krawtchenko et al. reported an initial complete clearance rate of about 68% with cryosurgery, but at 1 year of follow-up, only 4% of treated patients had sustained clearance of the treatment field.
Cryosurgery has an additional drawback. In addition to being ineffective against subclinical AK lesions, it is a painful procedure that is generally too painful or costly to treat all clinical or visible AK lesions in a single procedure. Thus, practitioners generally must choose at the time of treatment as to which AK lesions will be cryosurgically removed. Consequently, it is often that several clinical AK lesions go untreated requiring further cryosurgery sessions at some point in the future depending upon provider restrictions and patient tolerance. It is also often the case that because cryosurgery can be a very painful procedure, many patients fail to follow-up with treatment of the remaining clinical and subclinical AK lesions.
Field-directed treatments such as imiquimod, diclofenac and 5-fluoruracil treat both individual AKs as well as a field of cancerization. Imiquimod is a Toll-like receptor 7 agonist that has been shown to be safe and effective for the treatment of AKs. Gaspari A et al., J Drugs Dermatol 2009; 8:467-74; Lebwohl M et al., J Am Acad Dermatol 2004; 50:714-21; Swanson N et al., J Am Acad Dermatol 2010; 62:582-90; Hanke C W et al., J Am Acad Dermatol 2010; 62:573-81. In addition, imiquimod treatment appears to treat subclinical lesions, contributing to a high rate of sustained complete clearance of the treatment field. Krawtchenko N et al, Br J Dermatol 2007; 157(Suppl 2):34-40.
Imiquimod has a molecular formula of C14H16N4 and a molecular weight of 240.3. The chemical structural formula for imiquimod is as follows:

Imiquimod, also known as 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine and also known as (aka) 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, is commercially available, e.g., as ALDARA 5% imiquimod cream, as now approved by the U.S. Food & Drug Administration (“FDA”). In addition, ZYCLARA® is a lower dosage 2% or 3.75% imiquimod cream. ZYCLARA® can be used to treat actinic keratosis with shorter durations of therapy, than currently prescribed for the commercially available ALDARA 5% imiquimod cream. Such lower dosage strength imiquimod formulations can be used to deliver an efficacious dose of imiquimod for treating actinic keratosis with an acceptable safety profile.
Imiquimod is disclosed in U.S. Pat. No. 4,689,338, among other things, and described therein as an antiviral agent and as an interferon inducer, which is incorporated herein by reference in its entirety. A variety of formulations for topical administration of imiquimod are also described therein. This U.S. Pat. No. 4,689,338 is incorporated herein by reference in its entirety.
U.S. Pat. No. 4,411,893 discloses, among other things, the use of N,N-dimethyldodecylamine-N-oxide as a skin penetration enhancer in aqueous systems, wherein this U.S. patent is incorporated herein by reference in its entirety.
U.S. Pat. No. 4,722,941 discloses, among other things, readily absorbable pharmaceutical compositions that comprise a pharmacologically active agent distributed in a vehicle comprising an absorption-enhancing amount of at least one fatty acid containing 6 to 12 carbon atoms and optionally a fatty acid monoglyceride. Such compositions are said to be particularly useful for increasing the absorption of pharmacologically active bases, wherein this U.S. patent is incorporated herein by reference in its entirety.
U.S. Pat. No. 5,238,944, U.S. Pat. No. 7,038,051, U.S. Pat. No. 6,693,113, U.S. Pat. No. 6,894,060, U.S. Patent Publication No. 2011/0021555 (U.S. Ser. No. 12/636,613), U.S. Patent Publication No. 2007/0123558, U.S. Patent Publication No. 2004/087614, and U.S. Patent Publication No. 2002/147210 disclose, among other things, topical formulations and/or topical delivery systems containing 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine or 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, wherein each are incorporated herein by reference in their entireties.
Currently, the FDA has approved a 5% imiquimod cream, commercially available under the brand name ALDARA®, to treat certain dermal and mucosal associated conditions, such as (1) the topical treatment of clinically typical, nonhyperkeratotic actinic keratosis (AK) on the face or scalp in immunocompetent adults, (2) topical treatment of biopsy-confirmed, primary superficial basal cell carcinoma (sBCC) in immunocompetent adults, and (3) the topical treatment of external genital and perianal warts/condyloma acuminate in patients 12 years or older. Each gram of the ALDARA 5% imiquimod cream contains 50 mg of imiquimod in an off-white oil-in-water vanishing cream base consisting of isostearic acid, cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, purified water, benzyl alcohol, methylparaben, and propylparaben. The ALDARA 5% imiquimod cream is packaged in single-use packets or sachets, each containing 250 mg of cream, equivalent to 12.5 mg of imiquimod.
Notwithstanding FDA approval, ALDARA 5% imiquimod cream treatment is not without limitation, including an unsimplified and lengthy dosing regimen. Generally speaking, the treatment regimen for actinic keratosis using FDA-approved ALDARA 5% imiquimod cream consists of applying the ALDARA 5% imiquimod cream two times per week for a full 16 weeks to a defined/limited treatment area on the face or scalp (but not both concurrently). The surface treatment area for ALDARA 5% imiquimod cream is limited to approximately 25 cm2 (e.g., a 5 cm×5 cm area, which may be of any shape; the treatment area does not have to be square) and is defined as one contiguous area. The number of AK lesions treated with ALDARA 5% imiquimod cream per treatment area is generally between about 4 and about 8. Because the treatment area is quite small, less than one single-use ALDARA packet or sachet (250 mg of total cream, of which 12.5 mg is imiquimod) is generally used per application. Inconsistencies in both compliance and therapeutic results frequently occur with the treatment of actinic keratosis with FDA-approved ALDARA 5% imiquimod cream due to the lengthy treatment period, i.e., 16 weeks, the complicated dosing regimen, i.e., twice weekly, and the high incidence of application site reactions.
An optimized 2.5% or 3.75% imiquimod cream formulation (ZYCLARA®, Graceway Pharmaceuticals, LLC, Bristol, Tenn.) has demonstrated efficacy and tolerability in treating large areas of AK-involved skin (full face or balding scalp), in a short regimen of two 2-week cycles of daily applications. Swanson N et al., J Am Acad Dermatol 2010; 62:582-90. As shown in U.S. Patent Publication No. 2011/0021555 (U.S. Ser. No. 12/636,613), use of ZYCLARA® 3.75% imiquimod cream, or use of 2.5% imiquimod cream, has been shown to overcome certain of the limitations associated with the treatment of actinic keratosis with FDA-approved ALDARA 5% imiquimod cream and addresses current medical needs for (1) a larger treatment area (full face or balding scalp: >25 cm2 vs. up to 25 cm2 for ALDARA 5% imiquimod cream), (2) a shorter treatment period, e.g., two 2-week or two 3-week treatment cycles with an interim 2-week or 3-week no-treatment period sandwiched between them, respectively, vs. the full 16-week treatment regimen for ALDARA 5% imiquimod cream), (3) a more intuitive dosing regimen (daily dosing vs. twice weekly dosing for ALDARA 5% imiquimod cream) and (4) less or a lower incidence of application site reactions. The disclosure of U.S. Patent Publication No. 2011/0021555 (U.S. Ser. No. 12/636,613) is incorporated by reference herein in its entirety as though set forth explicitly herein.
Photodynamic therapy (PDT) with aminolevulinic acid (ALA) 20% topical solution is approved as a lesion-directed treatment of minimally to moderately thick AKs using one or two treatment sessions. Piacquadio et al., Arch Dermatol. 2004; 140:41-6; see also Levulan® Kerastick prescribing information. ALA absorbed by AK cells is converted to protoporphyrin IX, a photosensitizer. Excitation of the porphyrin molecule with light results in generation of singlet oxygen that leads to formation of superoxide and hydroxyl radicals which induce necrosis and apoptosis of the targeted cells. Gold & Goldman, Dermatol Surg. 2004; 30:1077-83. Although approved as a lesion-directed therapy with overnight incubation, field-directed PDT with ALA using short incubation also appears to provide meaningful efficacy. Touma et al., Arch Dermatol. 2004; 140:33-40.
PDT with ALA followed by imiquimod 5% treatment appeared to result in a higher sustained rate in AK reduction during follow-up than with PDT alone. Shaffelburg, J Drugs Dermatol. 2009; 8:35-9. Sequential therapy with PDT with methyl aminolevulinate, another photosensitizer, followed by imiquimod 5% treatment has been reported for basal cell carcinoma (Devirgiliis Dermatol Online J 2008; 28; 14:25, Maden et al., J Plast Reconstr Aesthet Surg. 2009; 62:e368-72) and Bowen's disease (Vereecken et al., J Eur Acad Dermatol Venereal. 2006; 20:1397-9). Sequential treatment with imiquimod 5% followed by PDT with methyl aminolevulinate has also been reported in the treatment of vulvar intraepithelial neoplasia. Winters et al., Clin Cancer Res. 2008; 14:5292-9. There are, however, no publications in PubMed with respect to the safety and/or efficacy of using topical 5%, 3.75%, or 2.5% imiquimod prior to lesion or field-directed PDT in treating AKs.
Thus, notwithstanding the advancements in the treatment of actinic keratosis, there still remains a need for improved treatments for treating both clinical and subclinical AK lesions.